Temporally feathered radiation therapy

ABSTRACT

The effects of acute toxicity from a radiation procedure can be reduced without altering the radiation dose. Instead, a radiation procedure can be weighted to deliver certain amounts of radiation per day through temporal feathering. A target volume for a radiation procedure can be determined based on at least one image. The radiation procedure includes a total dose of radiation to be administered in a time period. An organ outside of the target volume at risk of acute toxicity from the radiation procedure can be determined based on the at least one image. A sequence plan that ensures the total dose of radiation is administered in the time period can be calculated. The sequence plan includes one day of a high fractional dose of radiation and four days of a low fractional dose of radiation. The sequence accomplishes temporal feathering of the radiation therapy procedure.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/541,181, filed Aug. 4, 2017, entitled “TEMPORAL FEATHERING AS AMETHOD OF NORMAL TISSUE TOXICITY REDUCTION IN INTENSITY MODULATEDRADIATION THERAPY.” This provisional application is hereby incorporatedby reference in its entirety for all purposes.

TECHNICAL FIELD

The present disclosure relates generally to radiation therapy and, morespecifically, to systems and methods for temporally feathering aradiation therapy procedure to reduce the effects of acute toxicitywithout altering the radiation dose.

BACKGROUND

Radiation therapy is a modality for cancer treatment involvingapplication of ionizing radiation to the tumor. The safe and effectiveapplication of radiotherapy aims to treat the patient's tumor tissue,while sparing the patient's healthy tissue from acute toxicity. Thedevelopment of intensity-modulated radiation therapy has made strides insparing the patient's healthy tissue from acute toxicity. However, evenwith intensity-modulated radiation therapy, the healthy tissue of manypatients still suffers from acute toxicity. While the healthy tissue hasthe ability to recover from acute toxicity, this recovery can take time.

Intensity-modulated radiation therapy delivers constant radiation dosesat a constant time interval. The constant time interval often does notprovide time for the healthy tissue to recover from acute toxicity. Sucha lack of recovery can lead to a decreased quality of life for thepatient, and may even lead to treatment breaks that may compromise tumorcontrol.

SUMMARY

The present disclosure relates generally to radiation therapy and, morespecifically, to systems and methods for temporally feathering aradiation therapy procedure to reduce the effects of acute toxicitywithout altering the radiation dose. Using temporally featheredradiation therapy, a certain radiation dose can be delivered whileproviding adequate time for the patient's tissue to recover from acutetoxicity.

In one aspect, the present disclosure can include a system thattemporally feathers a radiation therapy procedure to reduce the effectsof acute toxicity without altering the radiation dose. The systemincludes a non-transitory memory storing instructions; and a processorconfigured to execute the instructions. A target volume for a radiationprocedure can be determined based on at least one image. The radiationprocedure includes a total dose of radiation to be administered in atime period. An organ outside of the target volume at risk of acutetoxicity from the radiation procedure can be determined based on the atleast one image. A sequence plan that ensures the total dose ofradiation is administered in the time period can be calculated. Thesequence plan includes one day of a high fractional dose of radiationand four days of a low fractional dose of radiation.

In another aspect, the present disclosure can include a method fortemporally feathering a radiation therapy procedure to reduce theeffects of acute toxicity without altering the radiation dose. At leasta portion of the method can be performed by a system comprising aprocessor. The method includes receiving a radiation procedurecomprising a total dose of radiation to be administered in a timeperiod; determining a target volume for the radiation procedure based onat least one image; determining an organ outside of the target volume atrisk of acute toxicity from the radiation procedure based on the atleast one image; and constructing a sequence plan that ensures the totaldose of radiation is administered in the time period. The sequence planincludes one day of a high fractional dose of radiation and four days ofa low fractional dose of radiation.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features of the present disclosure will becomeapparent to those skilled in the art to which the present disclosurerelates upon reading the following description with reference to theaccompanying drawings, in which:

FIG. 1 is a block diagram illustration showing an example of a systemthat temporally feathers a radiation therapy procedure to reduce theeffects of acute toxicity without altering the radiation dose inaccordance with an aspect of the present disclosure;

FIG. 2 is a block diagram illustration showing an example of thecomputing device of FIG. 1 in greater detail;

FIG. 3 is a process flow diagram of an example method for temporallyfeathering a radiation therapy procedure to reduce the effects of acutetoxicity without altering the radiation dose in accordance with anotheraspect of the present disclosure;

FIGS. 4-5 are process flow diagrams of additional example methods fordelivering a temporally feathered sequence according to the method ofFIG. 3;

FIG. 6 shows a comparison of conventionally fractionated IMRT and TFRTbased on the biology effective dose (BED) model;

FIG. 7 shows a comparison and representation of NTCP andradiation-induced OAR toxicity between conventionally fractionated IMRTand TFRT with varying organ specific recovery rates (μ);

FIG. 8 shows a comparison and representation of NTCP andradiation-induced OAR toxicity between conventionally fractionated IMRTand TFRT with varying standard fractional doses (d_(s)); and

FIG. 9 shows a comparison of conventionally fractionated IMRT and TFRTwith respect to the standard fractional dose (d_(s)) and organ specificrecovery rate (μ).

DETAILED DESCRIPTION I. Definitions

Unless otherwise defined, all technical terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich the present disclosure pertains.

In the context of the present disclosure, the singular forms “a,” “an”and “the” can also include the plural forms, unless the context clearlyindicates otherwise.

The terms “comprises” and/or “comprising,” as used herein, can specifythe presence of stated features, steps, operations, elements, and/orcomponents, but do not preclude the presence or addition of one or moreother features, steps, operations, elements, components, and/or groups.

As used herein, the term “and/or” can include any and all combinationsof one or more of the associated listed items.

Additionally, although the terms “first,” “second,” etc. may be usedherein to describe various elements, these elements should not belimited by these terms. These terms are only used to distinguish oneelement from another. Thus, a “first” element discussed below could alsobe termed a “second” element without departing from the teachings of thepresent disclosure. The sequence of operations (or acts/steps) is notlimited to the order presented in the claims or figures unlessspecifically indicated otherwise.

As used herein, the term “radiation therapy” can refer to a type ofcancer treatment that uses beams of intense energy (e.g., X-rays,photons, and the like) to kill cancer cells by damaging the geneticmaterial that controls how cancer cells grow and divide.

As used herein, the term “radiation procedure” can refer to theindividualized process utilized to apply radiation therapy to a patient.A certain dose of radiation can be administered to a target volume inthe patient for a certain time period. In addition to the target volume,one or more organs at risk may receive at least a portion of the dose ofradiation during the radiation procedure.

As used herein, the term “target volume” can refer to athree-dimensional portion of tissue to be treated during a radiationprocedure. The target volume can include a tumor and may includeadditional tissue located near the tumor.

As used herein, the term “organ at risk” can refer to one or more organsor tissues that may be damaged during exposure to radiation during aradiation procedure.

As used herein, the term “dose” can refer to an amount of radiation tobe administered the target volume during a radiation procedure given inunits of Gray (Gy). One Gy is defined as the absorption of one Joule ofradiation energy per kilogram of matter. Radiation dose can varydepending on the type and stage of cancer being treated and the locationof the cancer in the patient.

As used herein, the term “acute toxicity” can refer to adverse effectsof radiation exposure experienced by tissues and organs outside of thetarget volume.

As used herein, the term “fractional dose” can refer to a portion of aprescribed radiation therapy dose that is administered to a patient atintervals within a given time period. The sum of the fractional doseswithin the given time period make up the prescribed radiation therapydose.

As used herein, the term “sequence plan” can refer to a plan toadminister fractional doses over a given time period. Within thesequence plan, a sum of the fractional doses over the given time periodmust equal the prescribed radiation therapy dose.

As used herein, the term “intensity-modulated radiation therapy (IMRT)”refers to a radiation procedure that involves an even split of aprescribed radiation therapy into equal fractional doses within a giventime period.

As used herein, the term “temporal feathering” can refer to a radiationprocedure that involves a split of a prescribed radiation therapy intounequal fractional doses within a given time period. Temporal featheringcan include applying at least one relatively high fractional dosecompared to a standard fractional dose and then delivering a pluralityof relatively lower fractional dose compared to the standard fractionaldose. The lower fractional doses offset the greater radiation-induceddamage of the least one higher fractional dose.

As used herein, the term “image” can refer to a visual representation ofthe interior a patient's body for clinical analysis and medicalintervention. Images used in the medical field can include X-rays, CTscans, PET Scans, ultrasounds, and MRIs.

As used herein, the terms “subject” and “patient” can be usedinterchangeably and refer to any warm-blooded organism including, butnot limited to, a human being, a pig, a rat, a mouse, a dog, a cat, agoat, a sheep, a horse, a monkey, an ape, a rabbit, a cow, etc.

II. Overview

The present disclosure relates generally to radiation therapy. Strideshave been made to spare a patient's healthy tissue from acute toxicitywhile the patient undergoes radiation therapy to cure cancer.Intensity-modulated radiation therapy delivery constant radiation dosesat a constant time interval. With intensity-modulated radiation therapy,however, the healthy tissue of many patients still suffers from acutetoxicity because adequate time is not permitted for complete recoveryfrom acute toxicity. Such a lack of recovery can lead to a decreasedquality of life for the patient, and may even lead to treatment breaksthat may compromise tumor control

The present disclosure aims to provide this time for recovery while notimpairing the radiation therapy according to the prescribed dose. Thisis accomplished by optimizing the temporal dimension through which theradiation therapy is delivered to the patient and increasing the timefor recovery from acute toxicity through a treatment planning strategycalled temporal feathering. Accordingly, the present disclosure relates,more specifically, to systems and methods for temporally feathering aradiation therapy procedure to reduce the effects of acute toxicitywithout altering the radiation dose. Using temporal feathering, thepresent disclosure creates an interfractional interval that facilitatesrecovery of the radiation-induced damage in healthy tissue, while stillproviding the prescribed dose of radiation therapy.

III. Systems

One aspect of the present disclosure can include a system 10 (FIG. 1)that temporally feathers a radiation therapy procedure to reduce theeffects of acute toxicity without altering the radiation dose. Temporalfeathering the radiation therapy procedure, at its core, alters the timeframe of the radiation therapy procedure to give an organ at risk timeto recover from the radiation (e.g., when radiation is delivered by amulti-dimensional distribution of radiation sources, the time averagingbetween the different radiation sources can be changed to ensure thatthe prescribed radiation dose is delivered, but to limit the exposure ofthe organ at risk so that the organ at risk has time to recover fromacute toxicity). As such, the acute toxicity does not build up in theorgan at risk, which can potentially lead to a decreased quality of lifeand even treatment breaks that may compromise tumor control.

The system 10 can include a radiation delivery device 2 and a computingdevice 4. The computing device 4 can configure the radiation procedurewith the temporal feathering. The radiation delivery device 2 candeliver the radiation according to the radiation procedure with thetemporal feathering. The radiation delivery device 2 can communicatewith the computing device 4 in at least one direction (computing device4 to radiation delivery device 2) according to a wired and/or wirelessconnection. In this case, the radiation delivery device 2 can receivethe configured radiation procedure from the computing device 4. In someinstances, the communication can be in two directions, allowing feedbackfrom the radiation delivery device 2 to the computing device 4. Inresponse to the feedback, the computing device 4 may update theradiation procedure.

The computing device 4 can have peripheral devices, including (but notlimited to) an input 6 and a display 8. The input 6 can allow a user orother entity (like the radiation delivery device 2) to deliverinformation to the computing device 4. The display 8 can be used toprovide perceivable information regarding the radiation procedure. Theperceivable information can be a graphical display of a sequence planfor the radiation procedure. The perceivable information can also be agraphical display of an image to create the sequence plan. However, theperceivable information can be anything related to the radiationprocedure displayed in audible or visual form.

A patient diagnosed with cancer can be prescribed a total dose ofradiation to be administered to the tumor over a time period. Thecomputing device 4 can determine the proper sequence plan foradministration of the total dose over the time period. The computingdevice 4 aims to deliver the total dose to the tumor over the timeperiod with a minimal risk of acute toxicity to organs at risk. Thecomputing device 4 performs this risk management analysis using theconfiguration of the computing device 4 shown in FIG. 2.

The computing device 4 can receive (via the input 6) a radiationprocedure that includes a total dose of radiation to be administered toa patient in a time period. The total dose can be selected frompreviously used total doses (for the patient and/or other patients)based on a type of cancer, a size of cancer, a stage of cancer. As shownin FIG. 2, the computing device 4 can construct a sequence plan for thetotal dose during the time period. The computing device 4 includes anon-transitory memory 12 storing instructions and a processor 14 toaccess the memory and execute the instructions. The instructions includea target volume selector 16, a risk calculator 17, and a plan calculator18.

The target volume selector 16 can determine the target volume for theradiation procedure based on at least one image of the patient (whichcan be stored in the non-transitory memory 12 and/or received fromanother location). The image of the patient can include at least aportion of an area that includes malignant cells. Several images can besewn together to show the entire area of malignant cells if need be, Theradiation procedure includes The image and the target volume can also beused by the risk calculator 17 to determine one or more organs outsidethe target volume at risk of acute toxicity from the radiationprocedure. The information about the target volume and the one or moreorgans at risk can be used by the plan calculator 18 in constructing thesequence plan that ensures the total dose of radiation is administeredin the time period, while delivering as little damaging radiation to theorgan at risk as possible to reduce the effects of acute toxicity. Thesequence plan developed by the plan calculator can include one day of ahigh fractional dose of radiation and the other days including a lowfractional dose of radiation. The total dose can equal a sum of the highdose plus the number of low doses. This ensures that the total dose isdelivered, but gives the organ at risk sufficient time to recover fromacute toxicity due to the high dose before a high dose is deliveredagain.

The computing device 4 sends the sequence plan to a computer associatedwith the radiation delivery device 2. The computer associated with theradiation delivery device can be the computing device 4, but may be anadditional computing device. The radiation delivery device 2 deliversthe total dose of radiation to the patient according to the sequenceplan for the time period. The computer associated with the radiationdelivery device 2 can transmit information associated with the sequenceplan back to the computing device 4. The computing device 4 candetermine a new sequence plan for the next time period taking intoaccount the information from the radiation delivery device.

IV. Methods

As shown in FIG. 3, another aspect of the present disclosure can includea method 30 for temporally feathering a radiation therapy procedure toreduce the effects of acute toxicity without altering the radiationdose. FIGS. 4 and 5 show additional example methods 40, 50 fordelivering a temporally feathered sequence according to the method 30 ofFIG. 3. The methods 30-50 can be performed at least in part by thesystem 10 shown in FIGS. 1 and 2.

The methods 30-50 are illustrated as process flow diagrams withflowchart illustrations. For purposes of simplicity, the methods 30-50is shown and described as being executed serially; however, it is to beunderstood and appreciated that the present disclosure is not limited bythe illustrated order as some steps could occur in different ordersand/or concurrently with other steps shown and described herein.Moreover, not all illustrated aspects may be required to implement themethods 30-50. The methods 30-50 can be executed by hardware—forexample, at least a portion of the system 10 shown in FIGS. 1-2. One ormore hardware elements of the system 10 can execute software routines toimplement at least a portion of the methods 30-50. Additionally, one ormore elements of the system 10 can include a non-transitory memorystoring the software routines and one or more processors to execute thesoftware routines corresponding to the at least the portion of themethods 30-50.

Referring now to FIG. 3, illustrated is a method 30 for temporallyfeathering a radiation therapy procedure to reduce the effects of acutetoxicity without altering the radiation dose. The method 30 can besystem by a system (e.g., system 10) including a processor (e.g.,processor 14).

At 32, a radiation procedure can be received. The radiation procedurecan include a total dose of radiation to be delivered to a patient in atime period. For example, the time period can be a week (e.g., 5 days)and the radiation procedure can include the total dose to be deliveredin the week. The total dose can be split (or fractionated) for deliveryto the patient during the week.

At 34, a target volume for the radiation procedure can be determined (orconfirmed). The target volume, which can include one or more malignantcells, can be determined based on at least one image. At 36, an organoutside the target volume at risk for acute toxicity from the radiationprocedure can be determined. The organ at risk can also be determinedbased on the at least one image. It should be noted that additionalorgans at risk can be identified.

At 38, a sequence plan that ensures the total dose of radiation isadministered in the time period, while decreasing the risk of acutetoxicity to the organ outside the target volume. The sequence plan canminimize the risk of acute toxicity to the organ outside the targetvolume. In the sequence plan, the total dose can be fractionatedaccording to a temporal feathering procedure. For example, during a timeperiod of a week (5 days), the total dose (TD) can be fractionated withone day of a high fractional dose (HFD) and the other days can receive alow fractional dose (LFD) so that TD=HFD+4 LFD. In other words, the highfractional dose of radiation can be greater than ⅕ times the total doseof radiation and the low fractional dose can be less than ⅕ times thetotal dose of radiation. The high fractional dose of radiation and thelow fractional dose of radiation can be chosen based on a recovery rateof the organ outside of the target volume from acute toxicity. Withtemporal feathering, the total dose can be greater than a uniform totaldosage delivered to the target area according to a sequence planassociated with uniform fractional doses of radiation.

Referring now to FIG. 4, illustrated is a method 40 for administering atemporally feathered radiation procedure. The method 40 can be performedby radiation delivery device 2 of the system 10. At 42, a sequence planfor a time period can be received. At 44, radiation can be administeredaccording to the sequence plan for the time period. At 46, an editedsequence plan can be administered for the next time period. As anexample, the time period can be a week, so that the sequence plan can befollowed for the week. After administration for the week, the patient'sresponse can be studied, and a revised sequence plan can be createdbased on the patient's response.

Referring now to FIG. 5, illustrated is a method 50 for administering atemporally feathered radiation procedure. The method 40 can be performedby radiation delivery device 2 of the system 10. The method 40 shows oneexample of using temporal feathering in connection with four organs atrisk. It should be noted that a greater or fewer number of organs atrisk may exist and the method 40 can be changed accordingly.

At 52, a first sequence plan can be administered (by a multi-dimensionalradiation delivery source) with radiation at a first distribution for afirst time. At 54, a second sequence plan can be administered withradiation at a second distribution for a second time. At 56, a thirdsequence plan can be administered with radiation at a third distributionfor a third time. At 58, a fourth sequence plan can be administered withradiation at a fourth distribution for a fourth time.

V. Experimental

The following example is for the purpose of illustration only is notintended to limit the scope of the appended claims.

Through the years, researchers in the field of radiation oncology andmedical physics have been innovating new ways of widening thetherapeutic window by either increasing tumor control probability (TCP)or decreasing the normal tissue complication probability (NTCP). Recentworks have shown the potential of spatiotemporal fractionation schemesdelivering distinct radiation dose distribution in different fractionsto improve the therapeutic ratio. The goal has been to maximize the meanBED of the tumor and minimize the mean BED in normal tissue byhypofractionating parts of the tumor while delivering approximatelyidentical doses to the surrounding normal tissue. This planning strategyhas been shown to result in spatiotemporal fractionation treatments thatcan achieve substantial reductions in normal tissue dose. However, theeffect of interfractional normal tissue recovery of radiation-induceddamage has not been taken into account, which when considered could leadto further reduced treatment side effects.

This example demonstrates a treatment planning strategy referred to astemporally feathered radiation therapy that takes the effect ofintrafractional normal tissue recovery of radiation-induced damage intoaccount to optimize toxicity profiles without compromising tumorcontrol. Using temporally feathered radiation therapy, time can beleveraged to maximize the recovery of normal tissue from acute toxicitywithout altering total radiation dose (allowing, nonintuitively, formore occasional sublethal damage repair and prolonged repopulationphases even in the face of higher total dose delivered at the end oftreatment). The total radiation dose can be delivered as a specificrepetitive sequence defined with one higher than standard fractionaldose followed by a plurality of lower fractional doses for a time. Theplurality of lower fractional doses creates an interval between thehigher than standard fractional doses, allowing more time for recoveryfrom acute toxicity. Increasing the time for recovery can lead toimproved patient quality of life, as well as a potential for doseintensification

Methods

Temporally Feathered Radiation Therapy

The treatment planning strategy that will be discussed is termedtemporally feathered radiation therapy (TFRT). Using TFRT, thefractional radiation dose delivered to organs at risk (OARs) is alteredto allow for increased normal tissue recovery form radiation-induceddamage with respect to conventionally fractionated intensity-modulatedradiation therapy (IMRT). A TFRT plan is generated as a composite ofseveral iso-curative (i.e., same tumor dose) plans each with alteredconstraints on particular OARs of interest. In each of these TFRT plans,a single OAR would be deprioritized, allowing the optimization algorithmto reduce radiation dose and thereby toxicity to all other OARs.

In practice, a planning target volume (PTV) with five surrounding OARsof interest prescribed a standard dose of 70 Gy in 35 fractions, similarto that commonly implemented for head and neck cancers. Furthermore,consider that five treatment plans are developed, wherein each of thefive OARs receives a relatively high fractional dose (d_(H)) compared tothe standard fractional dose (d_(S)) once weekly, that is, 2.0 Gy. Arelatively lower (d_(L)) fractional dose is then delivered the remaining4 days of the week. With this treatment planning strategy, althoughgreater radiation-induced damage is induced by d_(H) once weekly, it isoffset by the lower fractional dose, d_(L), delivered over a greateramount of time—during the remaining 4 days. The composite of d_(H) andd_(L) is then compared to the corresponding standard fractional dosed_(s) delivered to each OAR in a conventionally fractionated IMRT plan.In this hypothetical case, the TFRT plan is composed by 35 fractions,and each OAR of interest will receive 28 fractions of 0<d_(L)<d_(S) and7 fractions of d_(H)>d_(S)>0. Fractional doses d_(L) and d_(H) remainunaltered during the course of treatments. For demonstrative purposes,radiotherapy treatment plans that feather five OARs are considered,though any number of OARs can be chosen for temporally feathering.

Biologically Effective Dose Model

The Linear-Quadratic (LQ) model is currently the most widely useddose-response formulation in radiotherapy. The LQ model fits to in vitrocell survival experiments and incorporates the LQ behavior of theobserved cell survival curves. The linear component accounts for cellkilling by DNA double strand breaks (DSBs) due to a single hit ofradiation, whereas the quadratic component represents the lethal effectsof two separate ionizing events that eventually cause DSBs. Thesurviving fraction (SF) of cells after n fractions of a radiation dose dis given by:

SF(d)=e ^(−nd(α+βd))  Equation 1

where α (Gy⁻¹) and β (Gy⁻²) are tissue dependent radiosensitivityparameters.

It follows directly from the LQ model that the biological effect (E) ofn equally sized fractions of dose d is given by E=nd (α+βd). Thisequation can be manipulated to derive biologically effective dose (BED)calculations, which is a standard quantity allowing comparison ofvarious radiotherapy fractionation schemes. BED is dependent on inherentbiologic radiosensitivity of tissues, which is termed as the α to βratio, α/β. The BED is given by:

$\begin{matrix}{{BED} = {{nd}\left\lbrack {1 + \frac{d}{\frac{\alpha}{\beta}}} \right\rbrack}} & {{Equation}\mspace{14mu} 2}\end{matrix}$

The BED equation above applies to conventionally fractionated radiationplans in which a same fractional dose (i.e., a standard dose) isdelivered daily. The BED for a standard daily treatment fraction(BED_(S)) is given by:

$\begin{matrix}{{BED}_{S} = {n_{S}{d_{S}\left\lbrack {1 + \frac{d_{S}}{\frac{\alpha}{\beta}}} \right\rbrack}}} & {{Equation}\mspace{14mu} 3}\end{matrix}$

where n_(S) is the number of treatment fractions and d_(S) is theradiation dose per fraction. The BED of temporally feathered plansBED_(TF) is defined as follows:

$\begin{matrix}{{BED}_{TF} = {{n_{L}{d_{L}\left\lbrack {1 + \frac{d_{L}}{\frac{\alpha}{\beta}}} \right\rbrack}} + {n_{H}{d_{H}\left\lbrack {1 + \frac{d_{H}}{\frac{\alpha}{\beta}}} \right\rbrack}}}} & {{Equation}\mspace{14mu} 4}\end{matrix}$

where n_(L) and n_(H) refer to the number of lower dose (d_(L)) andnumber of higher dose (d_(H)) fractions, respectively. Lower dosefractions deliver a radiation dose less than what would be delivered ina conventionally fractionated IMRT plan, 0<d_(L)<d_(S). Similarly,higher dose fractions deliver a radiation dose higher than what would bedelivered in a conventionally fractionated IMRT plan, d_(H)>d_(S)>0.Fractional doses d_(L) and d_(H) remain unaltered during the course oftreatment and are homogeneously distributed on each OAR. The totalnumber of fractions and their time of delivery remains the same as inconventionally fractionated IMRT and TFRT plans, that isn_(S)=n_(L)+n_(H). Additionally, the tumor dose does not change, onlythe dose to OARs

BED-Based Comparison of Treatment Plans

The difference in the BED delivered by a conventionally fractionatedIMRT plan (S) of a standard dose d_(s) and a temporally feathered (TF)radiation therapy plan is defined as ΔBED=BED_(S)−BED_(TF).

Dynamical Model of Normal Tissue Complication Probability

A nonspatial dynamical model is used to simulate normal tissue responseto radiation. This is a form of NTCP modeling, which is a quantitativemeasure of radiation-induced detriment to normal tissues. The model isformulated as a logistic differential equation that describes therecovery of normal tissues (N) from sublethal radiation-induced damagegiven by:

$\begin{matrix}{\frac{dN}{dt} = {{\mu \; {N(t)}\left( {1 - {N(t)}} \right)} - {{\delta \left( t_{i} \right)}{{RT}(d)}{N(t)}\left( {1 - {N(t)}} \right)}}} & {{Equation}\mspace{14mu} 5}\end{matrix}$

where the organ-specific parameter μ>0 represents the recovery rate ofradiation-induced damage. Before radiation, the simulated OAR is attissue homeostasis with a 1% turnover rate, thus N(0)=0.99. ThenN(t)<N(0) represents the level of normal tissue damage by radiotherapy(small values of N(t) relate to severe damage), and (N(0)−N(t)) is usedas an indication of the radiation induced toxicity. The logisticdifferential Equation 5 used to model normal tissue recovery simulates adecay of toxicity to zero over time. This is based on clinicalobservations revealing that not all patients develop late toxicities,and, more importantly, that acute toxicities normally do go to zero onrather short time scales. Furthermore, this model is used to compareconventionally fractionated and temporally feathered radiotherapy plansunder the same conditions, which does not influence the ability tocompare planning techniques. The model was solved numerically in Matlab(www.mathworks.com).

The effect of radiation is included by the loss termδ(t_(i))RT(d)N(t)(1−N(t)) in Equation 5, where δ(t_(i)) is the Diracdelta function equal to one at the time of irradiation t_(i) and zerootherwise. The structure of this loss term models the growing effect ofradiation therapy with increasing number of treatment fractions. Infact, it is known that as treatment fractions accumulate the observedradiation-induced acute toxicities become increasingly apparent.Clinically normal tissue toxicities that increase in severity mid-wayand toward the end of radiation therapy treatments are observed. Thefunction RT(d)=(1−e^(−αd−βd) ² ) is based on the radiobiological LQmodel in Equation 1. More precisely, RT(d) represents the “injuredfraction” of normal cells receiving a radiation dose d, that is1−surviving fraction of cells. Thus, for low radiation doses, theinjured fraction of normal cells due to radiation must be small, therebyRT(d) must be close to zero. On the other hand, high radiation doseswill result in more killed normal cells for which RT(d) tends to one.Furthermore, both the delivery of each treatment fraction and responseto radiation are assumed to be instantaneous.

It should be noted that the LQ model is used to describe the immediateradiation response of normal tissue and a dynamical NTCP model todescribe normal tissue repair of radiation-induced damage duringfractions and over the entire treatment time.

NTCP-Based Comparison of Treatment Plans

The difference between OAR toxicity induced by a conventionallyfractionated IMRT plan (N_(S)(t_(end))) and a TFRT plan(N_(TF)(t_(end))) at the end of treatment t_(end) is denoted byΔNTCP=N_(S)(t_(end))−N_(TF)(t_(end)). Positive values (ΔNTCP>0) favorTFRT over IMRT plans.

Overall and Maximum Potential Benefit of TFRT over ConventionallyFractionated IMRT

The normal tissue toxicity reduction of TFRT over conventionally plannedIMRT is estimated by using a term referred to as overall potentialbenefit (OPB_(TF)). For any given combination of the organ-specificrecovery rate μ and the fractional radiation dose d_(S) delivered by aconventionally fractionated IMRT plan, OPB_(TF) is the ratio ofsimulated TFRT plans with 0<d_(m)≤d_(L)≤d_(S) and 0<d_(S)≤d_(H)≤d_(m)that result in ΔNTCP>0 and deliver higher total doses than thecorresponding IMRT plans. In this study, d_(m) and d_(M) are the minimumlower dose (d_(L)) and the maximum higher dose (d_(H)) considered togenerate the TFRT plans.

The maximum potential benefit (MAX_(TF)) of TFRT over conventionallyplanned IMRT is defined as the maximum ΔNTCP>0 of simulated TFRT plansdelivering higher total doses than the corresponding IMRT plans.

Results

BED Model Simulations

The BED model is considered to compare TFRT and conventionallyfractionated IMRT under varying conditions. To this end, an OAR wasconsidered at a physiologic equilibrium and characterized by an α/βratio of 3 Gy. Furthermore, TFRT plans were simulated withd_(m)≤d_(L)≤d_(S) and d_(S)≤d_(H)≤d_(M) consisting of 28 fractions(n_(L)) of d_(L)<d_(S) and 7 fractions (n_(H)) of d_(H)>d_(S), and thecorresponding conventionally fractionated IMRT plans delivering d_(S) in35 fractions. For illustrative purposes, d_(m)=(d_(S)−0.5 Gy) andd_(M)=(d_(S)+2.5 Gy) with a dose increment of 0.01 Gy between d_(m) andd_(S), as well as between d_(s) and d_(M).

FIG. 6 illustrates ΔBED=(BED_(S)−BED_(TF)) between different TFRT andconventionally planned IMRT plans (Equations 3 and 4). Irrespective ofd_(S), TFRT plans result only in a lower BED when the total dose (28d_(L)+7 d_(H)) delivered to the OAR of interest is less compared to thestandard IMRT plan (35 d_(c)). Further, combinations of d_(L) and d_(H)exist in which BED_(TF)>BED_(S) even when the total dose by TFRT plansis less than in the conventionally fractionated IMRT plan. These resultshold irrespective of the α/β ratio of the OAR of interest. The BEDformulation does not account for the effect of interfractional normaltissue recovery of radiation-induced damage, and therefore is not asuitable model to evaluate the potential benefit of TFRT. Thishighlights the need for models that account for the dynamic of normaltissue recovery from radiation-induced damage between treatmentfractions to access the feasibility of TFRT.

Dynamical NTCP Model Simulations

The normal tissue complication probability (NTCP) of TFRT compared toconventionally fractionated IMRT is simulated by implementing thedynamical NTCP model presented in Equation 5. The conditions are thesame those described as above with respect to the BED model simulations.NTCP model simulations reveal a range of treatment planning conditionsin which TFRT plans reduce radiation-induced toxicity to OARs comparedto conventional planned IMRT plans. These conditions are dependent ond_(L) and d_(H), as well as on the organ-specific recovery rates μ,associated with radiation-induced damage. This is shown in FIGS. 7 and8, which represent ΔNTCP for TFRT and conventionally fractionated IMRTplans with varying μ and d_(S) values, respectively. As exhibited byFIGS. 7 and 8, certain combinations of d_(L) and d_(H) delivering highertotal doses in TFRT plans as compared to conventionally fractionatedIMRT plans yet reduce the overall radiation-induced OAR toxicity (shownin the bottom panels of FIGS. 7 and 8). The therapeutic gain by TFRTplans increases as treatment progresses (shown in the top panels ofFIGS. 7 and 8). Furthermore, FIGS. 7 and 8 show the difference betweenOAR toxicity induced by conventional planned IMRT and TFRT plans at theend of treatment (ΔNTCP) is greater with decreasing values of μ andincreasing fractional doses d_(S). Thus, TFRT is more beneficial forreducing radiation-induced toxicity in OARs with low recovery rates μand receiving high standard fractional doses d_(S) with conventionalplanned IMRT.

FIG. 9 summarizes the impact of organ-specific treatment parameters onthe potential benefit of TFRT over conventionally fractionated IMRT. Foreach combination of μ and d_(S) considered, FIGS. 9 (a) and (b) show theoverall potential benefit (OPB_(TF)) and maximum potential benefit(MAX_(TF)) of TFRT plans over the corresponding IMRT plans. FIG. 9 showsthat while keeping one of d_(S) or μ constant and varying the other, theOPB_(TF) and MAX_(TF) of TFRT increase until a maximum level and thendecrease again. This suggests that for each OAR characterized by aspecific recovery rate μ, TFRT plans can be designed to reduce OARtoxicity if the standard fractional dose d_(S) delivered by aconventionally fractionated IMRT plans lies in a certain range.Furthermore, there exists an optimal dose d_(S) in that range for whichOAR toxicity reduction with TFRT is greater. Similarly, OARs receiving aspecific standard fractional dose d_(S) with conventional planned IMRTcan be temporally feathered if the recovery rate μ is in a certainrange. This evidences that both d_(S) and μ must be considered togetherwhen determining the OAR toxicity reduction from TFRT overconventionally planned IMRT.

From the above description, those skilled in the art will perceiveimprovements, changes and modifications. Such improvements, changes andmodifications are within the skill of one in the art and are intended tobe covered by the appended claims.

What is claimed is:
 1. A system comprising: a non-transitory memorystoring instructions; and a processor configured to execute theinstructions to: determine a target volume for a radiation procedurebased on at least one image, wherein the radiation procedure comprises atotal dose of radiation to be administered in a time period; determinean organ outside of the target volume at risk of acute toxicity from theradiation procedure based on the at least one image; and construct asequence plan that ensures the total dose of radiation is administeredin the time period, wherein the sequence plan comprises one day of ahigh fractional dose of radiation and remaining days in the time periodof a low fractional dose of radiation.
 2. The system of claim 1, whereinthe sequence plan is sent to a computing device associated with aradiation delivery device, wherein the radiation delivery devicedelivers the total dose of radiation to a patient associated with thetarget volume according to the sequence plan.
 3. The system of claim 1,wherein the processor is configured to determine a second organ outsidethe target volume at risk of acute toxicity from the radiation procedurebased on the at least one image; and construct a second sequence planthat ensure the total dose of radiation is administered in a second timeperiod, wherein the second sequence plan comprises one day of a highfractional dose of radiation and four days of a low fractional dose ofradiation delivered at a different distribution than the first sequenceplan.
 4. The system of claim 3, wherein the processor is configured todetermine a third organ outside the target volume at risk of acutetoxicity from the radiation procedure based on the at least one image;and construct a third sequence plan that ensure the total dose ofradiation is administered in a third time period, wherein the thirdsequence plan comprises one day of a high fractional dose of radiationand four days of a low fractional dose of radiation delivered at anotherdifferent distribution than the first sequence plan and the secondsequence plan.
 5. The system of claim 1, wherein the sequence plan isconstructed to reduce the risk of acute toxicity in the organ outside ofthe target volume while still delivering the total dose of radiation tothe target volume.
 6. The system of claim 1, wherein the target volumecomprises malignant cells.
 7. The system of claim 1, wherein the highfractional dose of radiation is greater than ⅕ times the total dose ofradiation to be administered in the time period and the low fractionaldose of radiation is less than ⅕ times the total dose of radiation. 8.The system of claim 7, wherein the high fractional dose of radiation andthe low fractional dose of radiation are chosen based on a recovery rateof the organ outside of the target volume from acute toxicity.
 9. Thesystem of claim 1, wherein the total dosage is greater than a uniformtotal dosage delivered to the target area according to a sequence planof uniform fractional doses of radiation.
 10. A method comprising:receiving, by a system comprising a processor, a radiation procedurecomprising a total dose of radiation to be administered in a timeperiod; determining, by the system, a target volume for the radiationprocedure based on at least one image; determining, by the system, anorgan outside of the target volume at risk of acute toxicity from theradiation procedure based on the at least one image; and constructing,by the system, a sequence plan that ensures the total dose of radiationis administered in the time period, wherein the sequence plan comprisesone day of a high fractional dose of radiation and remaining days of thetime period a low fractional dose of radiation.
 11. The method of claim10, further comprising sending, by the system, the sequence plan to acomputing device associated with a radiation delivery device, whereinthe radiation delivery device delivers the total dose of radiation to apatient associated with the target volume according to the sequenceplan.
 12. The method of claim 10, further comprising displaying, by thesystem, a graphical representation of the sequence plan on a graphicaldisplay device.
 13. The method of claim 12, further comprising:receiving, by the system, a confirmation of the sequence plan from aninput device; and upon receiving the confirmation, saving, by thesystem, the sequence plan for use in the radiation procedure.
 14. Themethod of claim 10, further comprising: determining, by a system, asecond organ outside the target volume at risk of acute toxicity fromthe radiation procedure based on the at least one image; andconstructing, by the system, a second sequence plan that ensure thetotal dose of radiation is administered in a second time period, whereinthe second sequence plan comprises one day of a high fractional dose ofradiation and four days of a low fractional dose of radiation deliveredat a different distribution than the first sequence plan.
 15. The methodof claim 14, further comprising: determining, by the system, a thirdorgan outside the target volume at risk of acute toxicity from theradiation procedure based on the at least one image; and constructing,by the system, a third sequence plan that ensure the total dose ofradiation is administered in a third time period, wherein the thirdsequence plan comprises one day of a high fractional dose of radiationand four days of a low fractional dose of radiation delivered at anotherdifferent distribution than the first sequence plan and the secondsequence plan.
 16. The method of claim 10, wherein the sequence plan isconstructed to reduce the risk of acute toxicity in the organ outside ofthe target volume while still delivering the total dose of radiation tothe target volume.
 17. The method of claim 10, wherein the target volumecomprises malignant cells.
 18. The method of claim 10, wherein the highfractional dose of radiation is greater than ⅕ times the total dose ofradiation to be administered in the time period and the low fractionaldose of radiation is less than ⅕ times the total dose of radiation. 19.The method of claim 18, wherein the high fractional dose of radiationand the low fractional dose of radiation are chosen based on a recoveryrate of the organ outside of the target volume from acute toxicity. 20.The method of claim 10, wherein the total dosage is greater than auniform total dosage delivered to the target area according to asequence plan of uniform fractional doses of radiation.